Indirectly acting gabamimetics
The distinction between directly and indirectly acting gabamimetics is often difficult to establish and certain drugs have the two types of action.
They increase the concentration of GABA in contact of its receptors by one or more mechanism: increased biosynthesis, decreased catabolism, reuptake inhibition.
By inhibing catabolism
Vigabatrin
Vigabatrin selectively inhibits GABA transaminase, and induces an increase of intracerebral GABA concentration. It is reserved for treatment of resistant epilepsies, particularly partial epilepsy either as an adjunct to another treatment or as single-drug treatment in particular for infantile spasms, for example West's Syndrome . Its plasma half-life is 5 to 8 hours; it is not metabolized in the body.
Recent studies showed that in animals vigabatrin decreases addiction to heroin, nicotine, alcohol, metamphetamine, probably by modulating dopamine release.
The adverse effects most frequently observed are drowsiness, tiredness, more rarely depression, irritability, headache, confusions, memory disturbances, diplopia, weight gain. The sustained use of vigabatrin can cause optic nerve damage and visual field constriction. An ophthalmologic examination before and during treatment is necessary. Vigabatrin increases urinary aminoadipic acid elimination by inhibiting its catabolism.
By increasing biosynthesis and inhibiting reuptake
Gabapentin
Gabapentin is an antiepileptic whose chemical structure presents an analogy with that of GABA. It increases GABA synthesis by enhancing glutamate decarboxylase activity and increases GABA release in synaptic cleft. It is eliminated by the kidney without forming metabolites. Its dosage must be reduced in patients with renal impairment. It is indicated in treatment of partial epilepsies with or without secondary generalized attack, either in single-drug treatment, or in combination with other antiepileptic insufficiently effective. It is also indicated in treatment of post-herpetic pains of adult.
Its principal adverse effects are drowsiness, dizziness, ataxia, nystagmus, headache, tremors and diplopia.
Pregabalin
Pregabalin or isobutyl-GABA could increase GABA synthesis by increasing glutamic acid decarboxylase activity but in fact its mechanism of action is poorly known. Certain studies suggest that it could act on voltage-dependant calcium channels. Its marketing is envisaged for treatment of neuropathic pains and partial epilepsies.
Tiagabine
Tiagabine is an antiepileptic which inhibits GABA reuptake by neurons and GABA uptake by glial cells. It is indicated in the treatment of partial epilepsies with or without secondary generalized attacks, resistant to other antiepileptics. Its most frequent adverse effects are dizziness, asthenia and drowsiness.
Stiripentol
Stiripentol, inhibitor of GABA reuptake, has antiseizure properties. It is indicated for treatment of infant severe myoclonic epilepsy, as a complement to valproate and clobazam, when they are insufficient to control attacks. Stiripentol inhibits two CYP450 isoenzymes: CYP2C19 and CYP3A4 and can thus cause drug interactions.
Valproic acid
Valproic acid is a major antiepileptic drug with a very broad spectrum and a complex mechanism of action: it has gabamimetic effect, glutamate antagonist effect and inhibits voltage-dependant sodium channels.
Its gabamimetic effect results from a rise of cerebral GABA concentration consecutive to increase in its synthesis by activation of GABA decarboxylase and decrease of its catabolism by inhibition of GABA transaminase. Valproic acid penetrates into the brain by the transport carrier of monocarboxylic acids; its transfer into brain is in competition with that of other acids such as lactate, pyruvate and hydroxybutyrate.
Valproic acid is frequently used because it is active in almost all forms of epilepsy. Its half-life is approximately 15 hours and its effective therapeutic plasma concentration is between 60 and 80 mg/L.
Its principal adverse effects are digestive disorders, nausea, vomiting, gastralgia, and, less frequent but more severe, hepatitis. Taken during the first months of pregnancy, it could increase the risk of malformations, labial cleft in particular.
Valproate |
DEPAKINE*, DEPAKENE* |
Sodium divalproate and valpromide are prodrugs of valproic acid, prescribed for the treatment of bipolar disorders when lithium is poorly tolerated or contra-indicated.
Note:
- Oxybate, previously called s odium gamma-hydroxybutyrate, often named GHB, was released on the market in France in injectable form under the name of GAMMA-OH and used in anesthesiology as a rapid-acting hypnotic of short duration, associate with an analgesic. It is no longer marketed in France but it is it in USA under the name Xyrem *, presentation for oral route, for the treatment of cataplexy (brutal loss of muscular tone) in patients with narcolepsy.
With low doses, about 10 mg/kg, it has benzodiazepine-like effects: anxiolytic effect, drowsiness, amnesia, hypotonia. In large doses, from 30 to 60 mg/kg, it induces agitation, confusion, loss of consciousness. It can have an euphoriant action, induce an addiction and is used by drug addicts.
Its mechanism of action is poorly known, (it requires high doses approaching 1g whereas certain benzodiazepines act with 1 mg), it may activate specific receptors called GHB receptors as well as GABA-B receptors. Gamma-hydroxybutyrate is present in low concentration in brain where it is synthesized from GABA. It is not known if it has a physiological role.
- Bicuculline is a competitive antagonist of GABA-A receptor and picrotoxine, a noncompetitive antagonist. They are convulsive agents not used in therapeutics. Alpha-thujone, present in essential oils of wormwood, Artemisia absinthium, which was used in a drink popular in Paris towards 1900 before being prohibited, is also an antagonist of GABA-A receptor and has stimulant and convulsive effects.
- Tetanic toxin, taken up by motor nerve terminations around the infected wound, migrates along axons to the spinal cord where it inhibits the release of GABA, which explains the muscular hytertony observed. Tetanic toxin is a zinc-dependant protease which hydrolyzes and inactives a synaptic protein necessary for the release GABA.
- Ivermectin is an antihelminthic used in the treatment of onchocercosis, Onchocerca volvulus, as well as intestinal infections with nematoda and filaria such as Wucheria bancrofti. Ivermectin, which is a macrocyclic lactone produced by Streptomyces avermitilis, elicits in parasites hypertonicity and death by interacting with GABA and glutamate receptor-channels. Ivermectin crosses blood-brain barrier little explaining why it has little neurological effects. Its principal adverse effects are allergic reactions linked to toxin release by parasites. Ivermectin could also be of interest for the treatment of head lice and scabies.
Ivermectin |
MECTIZAN* STROMECTOL* |
Abamectin has chemical and pharmacological properties close to those of ivermectin.
|
